Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac Gefs and Gaps

Hindawi Publishing Corporation BioMed Research International Volume 2015, Article ID 632450, 17 pages http://dx.doi.org/10.1155/2015/632450

Review Article Regulating Rac in the Nervous System: Molecular Function and Disease Implication of Rac GEFs and GAPs

Yanyang Bai, Xiaoliang Xiang, Chunmei Liang, and Lei Shi

JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Jinan University, Guangzhou, Guangdong 510632, China

Correspondence should be addressed to Lei Shi; [email protected]

Received 23 January 2015; Accepted 6 March 2015

Academic Editor: Akito Tanoue

Copyright © 2015 Yanyang Bai et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Rho family GTPases, including RhoA, Rac1, and Cdc42 as the most studied members, are master regulators of actin cytoskeletal organization. Rho GTPases control various aspects of the nervous system and are associated with a number of neuropsychiatric and neurodegenerative diseases. The activity of Rho GTPases is controlled by two families of regulators, guanine nucleotide exchange factors (GEFs) as the activators and GTPase-activating proteins (GAPs) as the inhibitors. Through coordinated regulation by GEFs and GAPs, Rho GTPases act as converging signaling molecules that convey different upstream signals in the nervous system. So far,morethan70membersofeitherGEFsorGAPsofRhoGTPaseshavebeenidentifiedinmammals,butonlyasmallsubset of them have well-known functions. Thus, characterization of important GEFs and GAPs in the nervous system is crucial for the understanding of spatiotemporal dynamics of Rho GTPase activity in different neuronal functions. In this review, we summarize the current understanding of GEFs and GAPs for Rac1, with emphasis on the molecular function and disease implication of these regulators in the nervous system.

1. Introduction exchange of bound GDP for GTP,enabling them to recognize and activate downstream effectors, and GTPase-activating Rho family GTPases constitute a distinct family of guanine proteins (GAPs), which suppress Rho GTPases by enhancing nucleotide-binding proteins which belongs to the superfam- their intrinsic rate of GTP hydrolysis to GDP. ily of Ras-related GTPases. Rho GTPases are key regulators of Two types of GEFs for Rho GTPases have been identified. the actin cytoskeletal dynamics, play crucial roles in various Dbl-(diffuseB-celllymphoma-)likeGEFs,theclassical aspects of brain development, and are implicated in a number GEFs, are characterized by the presence of a DH (Dbl homol- of neuropsychiatric and neurodegenerative diseases [1–5]. ogy) domain followed by a PH (pleckstrin homology) domain More than 20 mammalian members of Rho family GTPases [8]. The DH domain is known to be responsible for the cata- have been described, including Rho-like (RhoA, RhoB, and lytic exchange activity of Rho GEFs, whereas the PH domain RhoC), Rac-like (Rac1, Rac2, Rac3, and RhoG), Cdc42-like regulates lipid binding and membrane targeting. Another (Cdc42, TC10/RhoQ, TCL/RhoJ, Wrch1/RhoU, and Chp/ type of GEFs is the Dock (dedicator of cytokinesis) family Wrch2/RhoV), Rnd (Rnd1, Rnd2, and Rnd3/RhoE), Rho- atypical GEFs, which contains a Dock homology region BTB (Rho-BTB1 and RhoBTB2), RhoD, Rif/RhoF,and RhoH/ (DHR) 1-DHR2 module instead of the PH-DH module. TTF [6, 7]. Like all GTP-binding proteins, Rho GTPases con- DHR1-DHR2 module plays similar roles as PH-DH module, tain sequence motifs for binding to GDP or GTP, thus acting of which DHR1 is important for the phospholipid-binding as bimolecular switches, cycling between an inactive GDP- and membrane targeting of Docks, and DHR2 is responsible boundstateandanactiveGTP-boundstate.ActivityofRho foritsGEFactivity[9]. On the other hand, Rho GAPs are GTPases is tightly controlled by the coordinated action of two usually large multidomain proteins characterized by the pres- classes of regulatory proteins: guanine nucleotide exchange ence of a conserved Rho GAP domain and various function factors (GEFs), which activate Rho GTPases by catalyzing the domains [10]. A variety of GEFs and GAPs have been 2 BioMed Research International identified to govern the activity of Rho GTPases in neuronal cortical neurons, and both Rac1-regulated leading process development and to be associated with neurological diseases formation and JNK-regulated microtubule organization are [5, 11–13]. implicated in Tiam1-regulated neuronal migration [20]. Rac1 is one of the most well-studied Rho GTPases Moreover, Tiam1 acts as a converging transducer of a whichcontrolsawiderangeofcellulareventsofneuronal number of signals, including neurotrophins (such as nerve morphogenesis and motility [14]. Rac1 is a master protein that growth factor (NGF) and brain-derived neurotrophic factor directs actin polymerization and cytoskeletal changes through (BDNF)), ephrins, and Wnts, to regulate neurite outgrowth activating a series of signaling pathways, thus acting as a and neural differentiation21 [ –24]. Tiam1 is also involved in converging sensor molecule that conveys divergent upstream the development of the myelinating glial cells oligodendro- signals. To understand the spatiotemporally dynamic reg- cytesandSchwanncells,suggestingaroleofTiam1forthe ulation of Rac1 activity in the nervous system, this review myelination of neurons in both central and peripheral ner- summarizes the current findings of more than 30 Rac GEFs vous system [25, 26]. Moreover, the gene expression of Tiam1 (including both the Dbl-like and atypical GEFs) and GAPs isdownregulatedinspecificneuronaltypesinresponseto (Table 1). Both the molecular functions and the disease cocaine and oxygen/glucose deprivation, which is one of relevance of these regulators in the nervous system will be possible molecular changes that cause synaptic structural or discussed. Most of these Rac GEFs or GAPs also act on functional alterations in these pathological conditions [27, other Rho GTPases (such as RhoA or Cdc42) or even other 28]. subfamilies of Ras-related GTPases (such as Ras and Rab). Tiam2, also known as STEF (Sif- and Tiam1-like exchange For these regulators, we will emphasize their actions on Rac factor), is the second member of Tiam protein family. Tiam2 and will try to discuss how their actions on Rac or other is far less studied than Tiam1, and its neuronal function GTPases are differentially regulated. revealed thus far is the regulation of neurite outgrowth [29, 30]. In particular, protein kinase A (PKA) dependent phos- 2. Dbl-Like Rac GEFs phorylation of Tiam2 activates the Rac GEF activity of Tiam2, which is a critical signaling pathway underlying dibutyryl 2.1. Tiam. Tiam1 (T-lymphoma invasion and metastasis 1) is cAMP (dbcAMP) induced neurite extension of neuroblas- one of the most extensively studied Rac GEFs in nervous and toma cells [30]. other systems. Tiam1 is a well-known regulator for synapse formation and plasticity. Tiam1 interacts with both EphB 2.2. Trio and Kalirin. Trio and Kalirin (also known as Duo), receptors and the synaptic neurotransmitter receptors, N- both having several isoforms, are multidomain containing methyl-D-aspartate (NMDA) receptors, at the postsynaptic Rac GEFs that share high sequence homology. Trio is ubiqui- sites [15, 16]. The Rac GEF activity of Tiam1 is upregulated tously expressed and plays critical roles in early development 2+ by CaMKII (Ca /Calmodulin-dependent protein kinase II) of the nervous system, whereas Kalirin is specifically enriched dependent phosphorylation and EphB activation, leading to in brain and elicits essential regulatory effects on synapse elevated Rac1 activity and spine formation [15, 16]. Moreover, morphogenesis and function. Tiam1 forms a complex with Par3 (partitioning defective gene Mice with complete deletion of Trio display embryonic 3), a regulatory protein for cell polarization, and is restricted lethality with malformed myofibers and defective organiza- to the synapse. This regulation is important for the local acti- tions in several brain regions including hippocampus and vation of Rac1 and spine morphogenesis [17]. Interestingly, olfactory bulb [31]. Further characterization of these Trio Tiam1 is also regulated by MAP1B (microtubule-associated knockout mice revealed that Trio transduces signaling from protein1B)andparticipatesinNMDA-inducedlong-term the chemoattractant netrin-1 through binding to the netrin- depression (LTD) through Rac1-dependent endocytosis of 1 receptor DCC (deleted in colorectal cancer), thus guiding AMPA (𝛼-amino-3-hydroxy-5-methyl-4-isoxazolepropionic the outgrowth and projection of commissure axons of cortical acid) receptors and spine shrinkage [18]. These seemingly neurons [32]. Trio is tyrosine phosphorylated by Fyn, a mem- contradictory findings of Tiam1 on both spine formation and ber of Src family kinases, in response to netrin-1 stimulation, elimination have been possibly explained by the following which is essential for DCC localization and netrin-induced study. Tiam1 interacts and cooperates with BCR (breakpoint Rac1 activation and axon growth [33]. Moreover, Trio is cluster region), a Rac GAP at the synapse, and the two coun- implicated in NGF-mediated neurite outgrowth via binding teract each other on Rac1 activity and spine morphogenesis to the membrane protein Kidins220/ARMS [34]. Several [19]. This Rac GEF-GAP complex possibly secures a dynamic neuronal isoforms of Trio have been identified and they also and balancing module for regulating spine structure, receptor exhibit activities on neurite outgrowth [35, 36]. To under- internalization, and synaptic plasticity, whereas disrupting stand the neuronal roles of Trio, mice with specific deletion of either component may cause abnormal activation of the Trio in the developing nervous system have been generated. other. These mice show remarkably reduced brain size and body Besides regulating synaptic function, Tiam1 plays multi- weight, severe ataxia, and neonatal death. Disrupted cerebel- faceted roles in developmental stages of the nervous system. lum development including aberrant granule cell migration Tiam1 is highly expressed in the intermediate zone and the and abnormal neurite growth is observed in these mice, cortical plate of developing cortex. The Rac GEF activity suggesting a critical role of Trio in cerebellum development of Tiam1 is required for the radial migration of newborn [37]. BioMed Research International 3

Table 1: Summary of Rac GEFs and GAPs in the nervous system.

Other targeted Name (aliases) Functions in the nervous system Upstream signals Neurological disease relevance GTPases Dbl-like Rac GEFs Spine morphogenesis; neuronal BDNF/TrkB; NGF/TrkA; migration; neurite outgrowth; Tiam1 NT3/TrkC; ephrinB1/EphB2; Cdc42 neural differentiation; glial cell Wnts; CaMKII myelination Tiam2 (STEF) Neurite outgrowth dbcAMP Cdc42 Axon guidance; neurite outgrowth; cerebellum Trio Netrin/DCC; NGF; Notch RhoA development; neuronal cluster organization in hindbrain Alzheimer’s disease; ischemic Spine morphogenesis; synaptic EphB2; CaMKII; N-cadherin; stroke; schizophrenia; cocaine plasticity; learning and memory; Kalirin-7 5-HT serotonin receptors; addiction; attention deficit dendritic growth of 2A neuregulin/ErbB4 hyperactivity disorder; interneurons; regulation of iNOS Huntington’s disease Dendritic outgrowth and Kalirin-9 Schizophrenia RhoA branching; spine morphogenesis Dendritic outgrowth and Kalirin-12 RhoA branching; endocytosis Spine morphogenesis; axon and 𝛼-PIX dendrite branching; learning and Reelin X-linked mental retardation Cdc42 (ARHGEF6/Cool-2) memory Spine formation; presynaptic 𝛽-Pix vesicle positioning; GABA A CaMKII Cdc42 (ARHGEF7/Cool-1) receptor stabilization; neurite and dendrite outgrowth Dendritic arborization; spine Sema3A/PlexinA1; Farp1 (CDEP) morphogenesis; presynaptic Sema6A/PlexinA4; retinoids; active zone modulation SynCAM1 Farp2 (FIR/FRG) Axon guidance; dendrite growth Sema3A/PlexinA1, PlexinA4 Cdc42 Neurite outgrowth; neuronal P-Rex1 migration; cerebellum NGF; BDNF; ephrin-B1 development and function Cerebellum development and P-Rex2 PI3K function Neurite outgrowth; axon Ephrin/Eph; BDNF/TrkB; Vav2 Cdc42 guidance; spine development NGF/PI3K Neurite outgrowth; axon guidance; spine development; Ephrin/Eph; BDNF/TrkB; Vav3 cerebellum development; Schizophrenia Cdc42 NGF/PI3K GABAergic neuron transmission in brainstem Plekhg4 Cerebellar function Spinocerebellar ataxia RhoA; Cdc42 (puratrophin-1) GEFT Neurite and dendrite growth Retinoic acid; dbcAMP Cdc42 Neurite growth; synaptic Epilepsy; L-dopa-induced RasGRF1 plasticity; learning and memory; Ras dyskinesia striatal function Neurite growth; synaptic RasGRF2 plasticity; alcohol-induced Alcoholism Ras reinforcement Amyotrophic lateral sclerosis; Motoneuron protection; primary lateral sclerosis; Alsin endosomal trafficking; neurite Rab5 infantile-onset ascending outgrowth hereditary spastic paralysis 4 BioMed Research International

Table 1: Continued. Other targeted Name (aliases) Functions in the nervous system Upstream signals Neurological disease relevance GTPases Atypical Rac GEFs Dock1 (Dock180) Spine morphogenesis Netrin/DCC; RhoG Microglia function and A𝛽 Dock2 Prostaglandin E2 Alzheimer’s disease deposition Alzheimer’s disease; Axonal outgrowth; Dock3 (MOCA/PBP) BDNF/TrkB glaucoma; attention deficit neuroprotection hyperactivity disorder Neurite and dendrite Autism; dyslexia; Dock4 development; spine Retinoic acid schizophrenia morphogenesis Dock6(Zir1) Axonalgrowthandregeneration Cdc42 Neuronal polarity; cortical neurogenesis; Schwann cell Epileptic encephalopathy and Dock7 (Zir2) differentiation and myelination; Neuregulin/ErbB2, ErbB4 Cdc42 cortical blindness axon terminal development of chandelier cells Rac GAPs Dendrite growth; spine morphogenesis; astroglia BCR BDNF/TrkB Cdc42 development; learning and memory Dendrite growth; spine morphogenesis; astroglia ABR Cdc42 development; learning and memory 𝛼1-Chimaerin Dendrite and spine development Diacylglycerol Duane’s retraction syndrome (n-chimaerin) Axon guidance in oculomotor Ephrin/Eph; Sema3/PlexinA; 𝛼2-Chimaerin and motor system; neuronal Duane’s retraction syndrome BDNF/TrkB; CXCL12; HGF migration; cognitive function 𝛽2-Chimaerin Axonal pruning Sema3F Neuronal migration; spine srGAP2 (FNBP2) Slit/Robo; valproic acid Schizophrenia; epilepsy Cdc42 development; neurite outgrowth Spine development; synaptic plasticity; learning and memory; Hydrocephalus; X-specific srGAP3 neural progenitor cell Slit/Robo; valproic acid mental retardation; (MEGAP/WRP) differentiation and migration; schizophrenia; epilepsy neurite outgrowth ArhGAP4 Axon growth p250GAP Dendritic and spine (Grit/RICS/p250GAP/ morphogenesis; axon guidance BDNF; NGF/TrkA; leptin Schizophrenia RhoA; Cdc42 p200RhoGAP/GC- and branching; neurite GAP) outgrowth; neuronal migration PX-RICS Neurite outgrowth Spine morphogenesis; neurite Rich1 (Nadrin) outgrowth; astrocyte NGF RhoA; Cdc42 differentiation Spine morphogenesis and Rich2 synaptic plasticity SH3BP1 (3BP-1) Growth cone collapse Sema3E/PlexinD1 BARGIN ROS diminishing Alzheimer’s disease CrossGAP Axon guidance and spine Slit/Robo Cdc42 (CrGAP/Vilse) morphogenesis MgcRacGAP Neuronal migration (RacGAP1/Cyk4) BioMed Research International 5

Alternative splicing of the KALIRIN gene (KALRN)gen- in schizophrenia patients, and Kalirin-7 interacts with erates several transcripts encoding functionally distinct pro- several schizophrenia-related proteins. The localization of teins, among which Kalirin-7 is the most prevalent isoform Kalirin-7 and the duration of Rac1 activation are regulated in mature neurons. Kalirin-7 is one of the critical integrators by the schizophrenia-related factor DISC1 (disrupted-in- localized at the postsynaptic density of excitatory synapses to schizophrenia 1) [55]. Moreover, Kalirin-7 is a downstream promote activity-dependent dendritic spine morphogenesis. mediator of the schizophrenia-related neuregulin/ErbB4 sig- Kalirin-7 is regulated at the synaptic areas through several naling, regulating dendritic spine morphogenesis of cor- mechanisms. First, Kalirin-7 is targeted to the synaptic mem- tical pyramidal neurons and dendritic growth of cortical brane by interacting with synaptic proteins, such as PSD- interneurons [56, 57]. Importantly, a sequence variant of 95/PDZ-containing proteins and the N-cadherin adhesion KALRN found in schizophrenia patients encodes a Kalirin-7 molecule complex, leading to local activation of Rac1 and mutant with diminished Rac GEF activity, and this mutant spine formation [38, 39]. Second, Kalirin-7 is extensively fails to increase spine density and size [58]. Expression of phosphorylated at the postsynaptic density, indicating that Kalirin-9, on the other hand, was found to be upregulated it is a converging signaling target and dynamically regulated in schizophrenia subjects [49]. Moreover, Kalirin has been by multiple kinases at the synapses [40]. In particular, the shown as a converging modulator in various pathological Rac GEF activity of Kalirin-7 is activated by synaptic EphB2 conditions such as those induced by cocaine and ischemia receptors and CaMKII via tyrosine and threonine phos- [59–61]. phorylation, respectively [41, 42]. Moreover, Kalirin-7 is regulated by 5-HT2 serotonin receptors and participates in A 2.3. PIX. The PIX (p21-activated kinase (PAK) interacting serotonin-modulated spine size increase of cortical pyrami- exchange factor) protein family includes 𝛼PIX (ARHGEF6) dal neurons [43]. Besides regulating spine structure, Kalirin-7 and 𝛽PIX (ARHGEF7). 𝛼PIX/ARHGEF6 gene is one of the also binds to the neurotransmitter NMDA and AMPA recep- causative genes of X-linked intellectual disability (ID) [62]. tors and regulates their expressions and functions [42, 44]. 𝛼PIX is expressed primarily in the hippocampus and is local- To understand the in vivo roles of Kalirin-7 and other Kalirins ized to the postsynaptic density of excitatory neurons [63, insynapsestructureandfunction,micewithonlyKalirin- 64]. 𝛼PIX regulates spine morphogenesis through interacting 7 isoform deleted and mice with the KALRN gene deleted with the postsynaptic adaptor protein GIT1 (G-protein cou- (in which all the Kalirin isoforms are absent) were gener- pled receptor kinase-interacting protein 1) and activation of ated. Interestingly, different phenotypical abnormalities were Rac and PAK3 [63, 65]. In the early development of neurons, observed in these two lines of mice. For instance, spine mor- 𝛼PIX promotes axon and dendrite branching and participates phogenesis and glutamatergic neurotransmission in cortex, in dendritic Golgi translocation in response to reelin [66, 67]. but not hippocampus, are significantly reduced in KALRN 𝛼PIX knockout mice exhibit disrupted synaptic plasticity knockout mice, and these mice exhibit age-dependent behav- and a series of behavioral abnormalities, including impaired ioral deficits such as reduced working memory, sociability, spatialandcomplexlearningandlessbehavioralcontrolin prepulse inhibition, and hyperactivated locomotion [45]. By mildly stressful situations, resembling typical ID symptoms contrast, only modest alterations are observed in the hip- [64]. pocampus, possibly associated with impaired fear condition- 𝛽PIX plays roles at both excitatory and inhibitory ing in these mice [46]. On the other hand, Kalirin-7 knock- synapses. At excitatory synapse, 𝛽PIX forms a complex with out mice showed decreased spine density in hippocampus important postsynaptic molecules including Shank and GIT1 and abnormal anxiety-like behavior, but locomotion and and regulates synaptogenesis [68]. 𝛽PIX is phosphorylated spatial working memory are normal in these mice [47]. 2+ by CaMKII in response to neuronal activity induced Ca Since the expression of larger Kalirin isoforms, Kalirin-8, -9, influx, which causes activation of 𝛽PIX toward Rac1 and spine and -12, is upregulated in Kalirin-7 knockout cortex [47], the formation [69]. 𝛽PIX also forms a complex with cadherin, discrepancies in these two lines of mice suggest nonover- 𝛽-catenin, and scribble at presynaptic sites and regulates lapping functions of Kalirin-7 and other Kalirins. The larger synaptic vesicle positioning [70]. Interestingly, the GIT1 and Kalirin isoforms have an additional RhoA GEF domain, 𝛽PIX complex is also localized to inhibitory synapses and which may thus contribute to their unique functions [48]. regulates the synaptic stability of GABAA receptors [71]. Indeed, Kalirin-9 and Kalirin-12 specifically regulate den- The ability of 𝛽PIX in regulating both excitatory and inhib- dritic outgrowth and branching of cortical neurons, whereas itorysynapsessuggeststhatitmaybeanessentialmod- overexpression of Kalirin-9 surprisingly decreases spine size ulator of synaptic balance. Moreover, 𝛽PIX is involved in and density [49, 50]. Kalirin-12 is also implicated in dynamin- several signaling pathways that regulate neurite and dendritic dependent endocytosis in neuronal cells [51]. outgrowth [72–74]. This is controversial to a recent report Being a critical synaptic regulator, KALRN has been that 𝛽PIX knockdown has no effect on dendritic growth found as a high risk gene of a variety of neurological diseases and branching [66]. These observations may be due to [52]. Both gene and protein expressions of Kalirin were the presence of different isoforms of 𝛽PIX that may play decreased in the hippocampus of Alzheimer’s disease (AD) additional functions during neuronal development [66, 75]. patients in a study, and the lowered Kalirin level may contribute to higher iNOS (inducible nitric oxide synthase) activity observed in the hippocampal specimens of the 2.4. Farp. Farp (4.1, ezrin, radixin and moesin (FERM), patients [53, 54]. Moreover, KALRN expression is decreased RhoGEF (ARHGEF), and pleckstrin domain protein) family 6 BioMed Research International includes two closely related members, Farp1 and Farp2. Both AnumberofstudieshaverevealedthatVav2andVav3,inpar- Farps function as mediators of Semaphorin (Sema)/Plexin ticular Vav2, participate in diverse signaling pathways to reg- signaling. Farp1 interacts with PlexinA1 receptors and is ulate neurite outgrowth and branching in vitro and in Xeno- required for Sema3A-promoted dendritic arborization of hip- pus spinal neurons [86–88]. Investigation of Vav2 and Vav3 pocampal neurons, which is a neuronal activity-dependent single or double knockout mice has provided more infor- process [76]. Moreover, Farp1 is a responsive gene of mation about the functional roles of these proteins in the retinoids in the developing spinal cord, where it mediates nervous system. In early developmental stages, Vav2 and Vav3 Sema6A/PlexinA4 signaling induced dendritic growth of are found to mediate ephrin/Eph signaling regulated axon spinal motoneurons [77]. On the other hand, although Farp2 guidance of ipsilateral retinogeniculate projections [89]. Vav2 also binds to PlexinA1 receptors, this interaction is dimin- binds to activated EphA4 receptors and its Rac GEF activity ished by Sema3A during axonal repulsion of dorsal root was stimulated by ephrin-A1. Such regulation induces endo- ganglion (DRG) neurons [78]. Dissociation of Farp2 from cytosis of the ephrin/Eph complex and a subsequent growth PlexinA1 increases Farp2’s GEF activity toward Rac1 and sub- cone collapse of cultured retinal ganglion cells (RGCs). sequently activates other signaling events, leading to repul- Importantly, deletion of both Vav2 and Vav3 in mice results in sion and decreased adhesion of axons [78]. A recent study abnormal axon projection of RGCs to the dorsal lateral genic- dissected the functional roles of different cytoplasmic ulate nucleus. In later developmental stages, Vav2 and Vav3 domains of PlexinA4 and compared the requirement of Farp1 interact with TrkB receptors and are transiently activated and Farp2 in Sema3A/PlexinA4 signaling. It reveals that upon TrkB stimulation by BDNF, leading to the activation of Farp1 and Farp2 bind to PlexinA4 in different fashions, and Rac1 [90]. Vav2 and Vav3 are dispensable for basal dendritic only Farp2 is required for Sema3A/PlexinA4 induced growth spine formation but are required for BDNF-induced rapid cone collapse of DRG neurons and dendritic growth of corti- spine enlargement and theta-burst-stimulated LTP in hip- cal neurons [79]. Besides acting as an effector of Sema/Plexin pocampus [90]. Other abnormalities identified in Vav2/Vav3 signals, it is found that Farp1 interacts with SynCAM1 double knockout mice include delayed degeneration, revas- (synaptic cell adhesion molecule 1), a synaptogenic protein, cularization and regeneration of peripheral nerves, and optic and regulates synapse formation. Farp1 works together with neuropathy associated with ocular deficits that are highly SynCAM1 to promote spine morphogenesis through acti- resemblance of glaucoma-like phenotypes [91, 92]. vation of Rac1 and increase of F-actin polymerization in To address whether individual Vav plays nonoverlapping spine heads. Farp1 and SynCAM1 also activate a retrograde biological roles, single knockout mice of each Vav have been signaling on the modulation of presynaptic active zones [80]. generated. In particular, two additional functions of Vav3 in the nervous system have been found. First, Vav3, but not Vav2, contributes to the development of cerebellum [93]. 2.5. P-Rex. P-Rex (phosphatidylinositol (3,4,5)-trisphos- Vav3 regulates the precise timing of several developmental phate-dependent Rac exchanger) family, including P-Rex1 processes at postnatal stages, including dendritogenesis of and P-Rex2, is activated by both PI3K (phosphoinositide Purkinje cell and the survival and migration of the granule 3-kinase) and GPCRs (G-protein coupled receptors). P-Rex1 cells. In line with the morphological defects of cerebellum, is localized to the distal tips of neurites and axonal growth Vav3 knockout mice exhibit abnormalities in cerebellum- cones and regulates NGF-stimulated neurite outgrowth related behaviors such as motor coordination and gaiting pat- through activating Rac1 and Rac3 [81]. Moreover, P-Rex1 is terns [93]. Second, Vav3 specifically regulates the axon guid- expressed in the developing cortex and regulates both radial ance of a subset of GABAergic neurons in the ventrolateral migration and tangential migration of newborn pyramidal medulla (VLM), a brainstem area. This regulation controls neurons under the control of neurotrophins (such as NGF the precise GABAergic transmission in VLM, which is even- and BDNF) and ephrin-B1, respectively [82, 83]. tually important for the modulation of blood pressure and Expression of P-Rex2 in the brain is much more limited respiratory rates [94]. Moreover, it was recently found that and is most prominently expressed in cerebellar Purkinje VAV3 is a candidate gene for schizophrenia, pointing to the cells. Aberrant dendrite morphology of Purkinje cells was importance of investigating Vav3 in the molecular pathophys- observed in P-Rex2 knockout mice, associated with motor iology of schizophrenia [95]. coordination deficits. P-Rex1 and P-Rex2 double knockout mice exhibit more severe motor coordination defects together 2.7. Plekhg4. Plekhg4, a GEF enriched in adult cerebellum, with ataxia, abnormal posture, and gait [84]. This suggests has been identified to be linked with autosomal dominant that P-Rex1 and P-Rex2 cooperatively regulate cerebellum spinocerebellar ataxia, a heritable neurodegenerative disease function. Further studies using P-Rex1/2 double knockout [96]. When expressed heterologously in fibroblast cells, mice show that PI3K-P-Rex signaling is important for late Plekhg4 possesses general GEF activities toward RhoA, Rac1, phase long-term potentiation (LTP) at the parallel fiber- and Cdc42 and is capable of inducing actin-dependent for- Purkinje cell synapse in cerebellum [85]. mation of lamellipodia and filopodia [97]. The stability and subcellular localization of Plekhg4 can be regulated by the 2.6. Vav. Three mammalian Vavs, Vav1, Vav2, and Vav3, have chaperoncomplexofheatshockproteins[97]. Nonetheless, been identified in Vav protein family. Vav1 is preferentially the function of Plekhg4 in the nervous system, especially expressed in immune system, whereas Vav2 and Vav3 are thecerebellum,andhowitsdysfunctionleadstocerebellar more ubiquitous with higher expression in developing brain. impairments still await further characterization. BioMed Research International 7

2.8. GEFT. GEFT, a small GEF that contains primarily a outgrowth [119–124]. Both Rab5 and Rac1 contribute to these DH and a PH domain, is widely expressed in various brain functions mediated by Alsin. In particular, knockdown of regions. Overexpressed GEFT promotes dendrite and spine Alsin in cultured rat spinal motoneurons leads to reduced growth in hippocampal neurons and facilitates retinoic acid endosome size, abnormal protein trafficking, and elevated and dbcAMP induced neurite outgrowth in neuroblastoma neuronal death [121]. Activation of Rac1, but not Rab5, cells [98, 99]. Although GEFT may activate both Rac1 and rescues these defects in Alsin deficient neurons [121]. Thus, Cdc42, its effect on neurite growth is possibly via Rac1/PAK although Rab5 may contribute to Alsin-regulated endosomal pathway [98]. trafficking, Rab5 is not essentially required in Alsin-regulated neuronal functions. In agreement with this finding, the membrane and endosomal localization of Alsin is reciprocally 2.9. RasGRF. RasGRF protein family, including RasGRF1 and regulated by activated Rac1, suggesting that activation of Rac1 RasGRF2, has dual GEF activities toward both Ras and Rac may be a signaling event prior to that of Rab5 [125, 126]. and is expressed predominantly in mature neurons. RasGRFs Moreover, the Rac GEF activity, in particular Rac1/PI3K/Akt3 play multiple roles in neurite outgrowth, synaptic plasticity, pathway, is involved in Alsin-regulated protective effects and neuronal behaviors [100, 101]. In particular, RasGRF1 against motoneuron death induced by mutant forms of SOD1 exhibits differential roles in regulating LTD, LTP, and dentate (superoxide dismutase 1), another causative gene in ALS gyrus neurogenesis in an age-dependent manner [102, 103]. [120, 127]. Rac1/PAK pathway is also important for Alsin- RasGRF1 directly couples to NMDA receptor 2B subunits regulated neurite outgrowth [119]. However, Alsin knockout (NR2B) to participate in the induction of LTD and dendrite mice exhibit no obvious motoneuron death and only mild complexity development [102, 104, 105]. On the other hand, motor defects [118]. The poor recapitulation to phenotypes association of RasGRF2 with NMDA receptor 2A subunits in human diseases may be due to compensatory effects from (NR2A) is required for LTP generation [102, 106]. As critical other ALS-related genes such as SOD1. Indeed, loss of ALS2 in mediatorsofsynapticfunction,bothRasGRFsarefoundtobe aALS-relatedSOD1 mutant mice exacerbates neurotoxicity, essentially involved in physiological and pathological neural accumulation of misfolded proteins, and motor dysfunction behaviors. For instance, RasGRF1 regulates learning and of the mutant mice [128]. memory and is implicated in epilepsy, striatum-dependent motor behavioral deficits induced by cocaine, L-dopa, or amphetamine [107–112]. RasGRF2 is important for contextual 3. Dock Family Atypical Rac GEFs discrimination and is found to be a responsible molecule for Dock (dedicator of cytokinesis) protein family is a family of alcohol-induced reinforcement [113, 114]. atypical GEFs which contains 11 members, of which Dock1– Given that RasGRFs activate both Ras and Rac1, detailed 5 activate Rac1 and Dock6 and Dock7 activate both Rac1 analysis has been performed to provide further information and Cdc42 [129]. Except Dock5, the other six members of about whether both small GTPases or only one of them is these Rac GEF activity-possessing Docks all have known important for specific RasGRF’s function. In particular, Rac1 functions in the nervous system. Dock1, also called Dock180, signaling is differentially activated in RasGRF1-mediated is involved in the regulation of axon guidance and dendritic LTD [102]. Similarly, although the Ras GEF activity of spine morphogenesis. Dock180 binds to the netrin receptor RasGRF2 regulates synaptic strength and NMDA current, DCC and mediates netrin-induced Rac1 activation and axon only its Rac GEF activity is activated immediately following growth [130]. Interestingly, Dock180 is also important for the stimulation of NMDA, which is in turn required for the rapid axon pruning induced by ephrin-B3 reverse signaling and spine enlargement and LTP generation [115]. Importantly, the RhoG, suggesting a bifaced role of Dock180 in axon attraction Rac GEF activity of RasGRFs may be differentially regulated and repulsion [131, 132]. Moreover, Dock180 promotes Rac1 by protein interaction and phosphorylation. For instance, activation and leads to dendritic spine morphogenesis in the Rac GEF activity of RasGRF1 is specifically inhibited by hippocampal neurons [133]. the microtubule-destabilizing factor SCLIP (SCG10-like pro- Dock2 is expressed exclusively in microglia and is impli- tein), which antagonizes the neurite outgrowth induced by cated in neuroinflammation of AD pathology. It has been RasGRF1 [116]. Moreover, the Rac GEF activity of RasGRF2 shown that the number of Dock2-expressing microglia is is decreased by p35/Cdk5 via phosphorylation [117]. abnormally increased in brains of AD patients and the expression of Dock2 is positively regulated by prostaglandin E2 2.10. Alsin. The gene encoding Alsin, ALS2,isacausative receptors [134]. Additionally, Dock2 deficiency significantly gene of several motoneuron degenerative diseases, including reduces the area and size of 𝛽-amyloid (A𝛽)plaqueincerebral juvenile amyotrophic lateral sclerosis (ALS), primary lateral cortex and hippocampus of a mouse model of AD [135]. sclerosis, and infantile-onset ascending hereditary spastic Dock3 plays major roles in neurite outgrowth and neuro- paralysis [118]. Alsin has dual GEF activities for both Rab5, protection and is implicated in several neurological diseases a member of Rab GTPases essential for protein trafficking such as AD and glaucoma [136]. Dock3 mediates several through early stages of the endocytic pathway, and Rac1. molecular events that are important for BDNF-induced AbatteryofstudiesincellsandinALS2 knockout mice neurite and axon growth [137, 138]. More importantly, Dock3 have revealed a broad range of cellular functions of Alsin, exerts several neuroprotective effects, whereas loss of Dock3 including protection of motoneuron survival, endosomal leads to axon degeneration [139]. Dock3 decreases the secre- trafficking of neuronal membrane proteins, and neurite tion of APP (amyloid precursor protein) and A𝛽 peptide 8 BioMed Research International by accelerating the proteasome-dependent degradation of [158]. The GAP activity of BCR can be promoted by phospho- 177 APP [140]. Moreover, Dock3 ameliorates the neurotoxicity rylation at its Tyr residue [160]. Fyn and protein tyrosine induced by NMDA receptors via interacting with the C- phosphatase receptor T (PTPRT) are the upstream kinase terminus of NMDA receptor subunits [141, 142]. These find- andphosphatase,respectively,thatregulateBCRactivityvia 177 ings suggest that Dock3 is a potential therapeutic target for targeting the Tyr residue [160]. nerve injury and degeneration. Indeed, two recent findings have shown that Dock3 stimulates neuroprotection after optic 4.2. Chimaerin. Chimaerins are a family of Rac GAPs which nerve injury and protects myelin in a demyelination model of contain a GAP domain homologous to that of BCR. Two multiple sclerosis [143, 144]. subfamilies of chimaerins, 𝛼-chimaerins encoded by CHN1 The gene encoding Dock4 has been found to be associated gene and 𝛽-chimaerins encoded by CHN2 gene, are identified with several neuropsychiatric diseases, including autism, in mammals. There are three alternative spliced products of dyslexia, and schizophrenia [145–147]. Dock4 regulates neu- each of CHN1 and CHN2: 𝛼1- and 𝛽1-chimaerins contain a C1 rite and dendrite outgrowth through Rac1-dependent actin domain and a GAP domain, 𝛼2- and 𝛽2-chimaerin possess cytoskeleton reorganization [148]. Dock4 is also important an additional SH2 domain at the N-terminus, and 𝛼3- and for spine morphogenesis of hippocampal neurons [149]. 𝛽3-chimaerin only contain a GAP domain [161]. Dock6 has been found to promote neurite outgrowth and Among the different members of chimaerins, 𝛼2- regulate axonal growth and regeneration of sensory neurons chimaerins are the most studied and have been revealed to [150, 151]. Although Dock6 is capable of activating both Rac1 play crucial functions in the nervous system. Mutation of the and Cdc42 in vitro, it preferentially activates Rac1 in DRG CHN1 gene is one of the causes of Duane’s retraction syn- neurons [151]. The GEF activity of Dock6 towards Rac1 is drome (DRS), a complex congenital eye movement disorder regulated by phosphorylation/dephosphorylation at Ser1194 caused by aberrant axonal innervation of the extraocular byAktkinaseandproteinphosphatasePP2A. muscle [162].Anumberofheterozygousmissensemutations Dock7 is highly expressed in the developing brain and in CHN1 have been found in DRS and all cause hyperacti- has been found to play important roles in several neuronal vation, that is, gain of function, of the GAP activity of developmental processes. Dock7 regulates the neurogenesis chimaerin and misguidance of oculomotor nerves [162]. in the neocortex by promoting the differentiation of radial Further molecular dissection has shown that 𝛼2-chimaerin glial progenitor cells into basal progenitors and neurons [152]. actsasadownstreammediatorofboththerepellentsignalsof Dock7 also plays a role in controlling neuronal polarity oculomotor axon guidance, that is, Sema3/PlexinA, and the and axon formation [153]. A recent study has revealed that attractant signals, that is, the chemokine CXCL12 and Dock7 is expressed in chandelier cells, an important type of hepatocyte growth factor (HGF) [163]. The ability of 𝛼2- interneurons for modulating cortical circuits, and regulates chimaerintorespondtobothpositiveandnegativesignals axonal terminal development of these cells under the control suggests that 𝛼2-chimaerin represents a balancing interme- of ErbB4 receptors [154]. Notably, mutations in DOCK7 diate which maintains the high sensibility of axons to the were found in individuals with epileptic encephalopathy and surrounding microenvironment. cortical blindness [155]. In the peripheral nervous system, Besides regulating axon guidance in oculomotor system, Dock7 is important for the development of Schwann cells, 𝛼2-chimaerin is also critical in the axon pathfinding of the glial cells that ensheath the axons of motor and sensory corticospinal tract and spinal cord neurons during motor neurons. Dock7 negatively regulates the differentiation of circuit assembly. 𝛼2-Chimaerin functions as an indispensable Schwann cells and the onset of myelination in both primary effector of ephrin/Eph repellent signaling pathway to restrict Schwann cells in vitro and sciatic nerves in vivo [156]. the axons to project into the ipsilateral side of the spinal Moreover, Dock7 promotes Schwann cell migration mediated cord without crossing the midline [164–167]. Such function by neuregulin-ErbB2 receptors [157]. of 𝛼2-chimaerin controls alternate body movement, whereas knockout of 𝛼2-chimaerin results in locomotion defects and 4. Rac GAPs involuntary synchronous arrhythmic stepping, known as a rabbit-like hopping gait [164, 166–168]. The molecular regula- 4.1. BCR and ABR. BCR and ABR (active BCR-related) are tion of 𝛼2-chimaerin activation includes membrane recruit- two closely related Rac GAPs expressed mainly in the brain. 𝛼 ABR and BCR have both GAP and GEF domains but only ment and tyrosine phosphorylation of 2-chimaerin by Eph exhibit GAP activity in vivo. Knockout of both ABR and BCR receptors and binding to the adaptor protein Nck family, or either of them in mice leads to elevated Rac1 activity in which leads to Rac1 in activation and growth cone collapse the brain [158, 159]. Defects observed in the knockout mice [164, 165, 169]. 𝛼 include functional and structural abnormalities of astroglia Interestingly, despite the hopping gait behavior, 2- in postnatal cerebellar development, increased dendritic chimaerin null mice exhibit enhanced contextual fear learn- arborization and spine number, and defective LTP mainte- ing. Such behavior abnormalities are only observed when nance in the hippocampus [158–160]. Moreover, BCR coexists 𝛼2-chimaerin is genetically deleted in early developmental with Tiam1 as a Rac GEF-GAP complex to regulate spine stages, but not in adulthood [170]. One of the roles of 𝛼2- morphogenesis and synaptic plasticity under the control of chimaerin in early development is the regulation of the radial BDNF-TrkB signals [19]. Either ABR or BCR knockout mice migration and positioning of newborn pyramidal neurons exhibit impaired spatial and object recognition memory during corticogenesis. Such regulation is a key determinant BioMed Research International 9 of normal cortical excitability and seizure threshold in adult- perinatal-onset hydrocephalus, which is possibly due to hood [171]. On the other hand, 𝛼1-chimaerin, the shorter cerebral aqueductal occlusion caused by abnormal migration splicing variant of 𝛼2-chimaerin, is enriched in later devel- and differentiation of progenitor cells from the ventricular opmental stages and is not involved in gait behavior or region into the corpus callosum [181, 183]. Studies in neurob- contextual fear learning [170]. 𝛼1-Chimaerin plays a role in lastoma cells and cultured embryonic neural progenitor cells pruning of dendritic branches and spines, and such effect may have confirmed that srGAP3 negatively regulates neuronal be regulated by synaptic activity and interaction with NMDA differentiation and neurite outgrowth [184, 185]. Such effect of receptors [172, 173]. srGAP3 may involve interaction with Brg1 (Brahma-related The function of 𝛽-chimaerins in the nervous system is gene 1), a modulator of chromatin remodeling enzymes, and less understood comparing to 𝛼-chimaerins. One report has an interplay of other srGAPs such as srGAP2 [186, 187]. Other revealed that 𝛽2-chimaerin acts as a mediator of Sema3F functions of srGAP3 include the positioning of commissural signalinginregulatingaxonalpruningindevelopinghip- axons of spinal cord neurons, possibly under the regulation pocampus [174]. of Slit-Robo signals [188].

4.3. srGAP. The Slit-Robo GAP (srGAP) family is an F- 4.4. p250GAP. p250GAP, also called RICS or Grit, shows BAR (Bin, Amphiphysin, and Rvs) domain containing GAP GAP activity toward inhibition of RhoA, Rac1, and Cdc42. family that has four members, srGAP1, srGAP2, srGAP3, p250GAP gene was recently found as a candidate gene for sus- and ArhGAP4. Among these members, srGAP1 preferentially ceptibility to schizophrenia, suggesting its potential impor- inhibits Cdc42, whereas srGAP2 and srGAP3 downregulate tance in brain development and function [189]. p250GAP Rac1. ArhGAP4 may be implicated in the inhibition of axon is a target of microRNA 132 (miR132), which downregulates growth, but its function has been largely unknown [175]. p250GAP expression and upregulates Rac1 activity in a man- srGAP2 negatively regulates radial migration of cortical ner dependent on neuronal activity. This miR132-p250GAP neurons through its F-BAR domain mediated increase of pathway is required for dendrite development, the hormonal leading process branching [176]. The GAP activity of srGAP2 regulator leptin-induced synaptogenesis, and BDNF-induced toward Rac1 partially contributes to srGAP2-induced neurite axon branching of RGCs during retinocollicular/tectal map branching and migration inhibition [176]. Moreover, srGAP2 formation [190–192]. On the other hand, p250GAP interacts promotes maturation of dendritic spines but decreases sine with and is recruited to spines by NMDA receptors, leading density in the neocortex [177]. Notably, it is found that to a modulation of RhoA activity and spine morphology [193, SRGAP2 isoneofthehuman-specificduplicatedgenes,which 194]. Moreover, functions of p250GAP dependent on RhoA undergoes incomplete duplications that generate several or Cdc42 have been revealed in regulating neurite/axon partial SRGAP2 products in the human brain [177, 178]. growth and neuronal migration of cortical neurons [195– srGAP2C, encoded by one of the major duplications, forms 197]. PX-RICS, a major isoform of p250GAP identified in the dimers with srGAP2 and inhibits srGAP2 function on nervous system, also regulates neurite extension [198]. migrating inhibition and spine maturation, suggesting that srGAP2 is modulated by its paralogs in human brain [177]. srGAP3, also called MEGAP (mental disorder asso- 4.5. Rich. Rich (Rho GAP interacting with Cdc42-interacting ciated GAP protein) or WRP (WAVE (Wiskott-Aldrich protein 4 homologues) protein family contains two mem- syndrome protein verprolin-homologous) associated Rac bers, Rich1 and Rich2. Rich1, also called Nadrin (neuron- GTPase-activating protein), is a factor linked to mental retar- associated developmentally regulated protein), shows GAP dation [179]. srGAP3 controls the early stages of dendritic activity toward RhoA, Cdc42, or Rac1. In particular, Rich1 spine formation in an F-BAR domain dependent manner interacts with PACSIN (protein kinase C and casein kinase 2 and is dispensable for the maintenance of spine density substrate in neurons), a neuronal adaptor protein, to regulate [180]. The in vivo functions of srGAP3 on synapse structure dendritic spine morphogenesis through modulating Rac1 andfunctionhavebeenrevealedinseverallinesofsrGAP3 activity [199]. Different splicing variants of Rich1 have been knockout mice. Mice with deletion of srGAP3 in brain show identified in neurons and some show inhibitory effects on deficits in multiple long-term learning and memory tasks, NGF-induced neurite outgrowth [200]. including novel object recognition, water maze, and passive Rich2 is a novel interacting protein of Shank3, a crit- avoidance [180]. In another study, a line of complete srGAP3 ical postsynaptic scaffolding protein. During LTP, Rich2- knockout mice show schizophrenia-like behaviors, such Shank3 interaction is increased in dendritic spines and the as impaired social behavior, working memory and pre- complex participates in exocytosis of AMPA receptor sub- pulse inhibition, more spontaneous tics, and exacerbated units through endosomal recycling [201]. Furthermore, Rich2 methylphenidate-induced locomotor hyperactivation [181]. specifically inactivates Rac1 in neurons and regulates den- However, the long-term memory is surprisingly normal in dritic spine morphogenesis [202]. these complete srGAP3 knockout mice. Moreover, srGAP3 interacts with the actin regulatory scaffold WAVE-1 and 4.6. SH3BP1. An RNAi screening identified SH3BP1 (SH3- regulates synapse morphogenesis and function. Mice with domain binding protein 1) as a downstream mediator of disrupted WAVE-1-srGAP3 interaction show decreased spine Sema3E/PlexinD1 signaling [203]. SH3BP1 binds to PlexinD1 density, elevated LTP, and impaired retention of spatial receptors at resting state and is released from PlexinD1 memory [182]. Notably, srGAP3 knockout mice exhibit complex upon Sema3E stimulation, which in turn leads to 10 BioMed Research International inactivation of Rac1 and cell collapse [203]. 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